Engineered liposomes for potential alpha-particle therapy of metastatic cancer

Disseminated, metastatic cancer is frequently incurable. Targeted alpha-particle emitters hold great promise as therapeutic agents for disseminated disease. (225)Ac is a radionuclide generator that has a 10-d half-life and results in alpha-emitting daughter elements ((221)Fr, (217)At, (213)Bi) that lead to the emission of a total of 4 alpha-particles. The aim of this study was to develop approaches for stable and controlled targeting of (225)Ac to sites of disseminated tumor metastases. Liposomes with encapsulated (225)Ac were developed to retain the potentially toxic daughters at the tumor site.

(225)Ac was passively entrapped in liposomes. To experimentally test the retention of actinium and its daughters by the liposomes, the gamma-emissions of (213)Bi were measured in liposome fractions, which were separated from the parent liposome population and the free radionuclides, at different times. Under equilibrium conditions the decay rate of (213)Bi was used to determine the concentration of (225)Ac. Measurements of the kinetics of (213)Bi activity were performed to estimate the entrapment of (213)Bi, the last alpha-emitting daughter in the decay chain.

Stable pegylated phosphatidylcholine-cholesterol liposomes of different sizes and charge were prepared. Multiple (more than 2) (225)Ac atoms were successfully entrapped per liposome. (225)Ac retention by zwitterionic liposomes was more than 88% over 30 d. Retention by cationic liposomes was lower. A theoretical calculation showed that for satisfactory (213)Bi retention (>50%), liposomes of relatively large sizes (>650 nm in diameter) are required. (213)Bi retention was experimentally verified to be liposome-size dependent. For large liposomes, the measured (213)Bi retention was lower than theoretically predicted (less than 10%).

This work supports the hypothesis that it may be possible to develop (225)Ac-based therapies by delivering multiple (225)Ac atoms in liposomes. Improvements in the retention of (225)Ac daughters will likely be necessary to fulfill this potential. Because of the size of the liposomal structures required to contain the daughters, the approach is ideally suited for locoregional therapy (e.g., intraperitoneal, intrahepatic artery, or intrathecal).